Deletion of concurrent chemotherapy on the basis of sequential chemoradiotherapy for non‐metastatic stage T4 nasopharyngeal carcinoma in IMRT era

Abstract Purpose Intensity‐modulated radiotherapy (IMRT) combined with concurrent chemotherapy is deemed as the mainstay treatment in locoregionally advanced nasopharyngeal carcinoma (NPC). Nevertheless, the tolerance of severe acute toxicity of concurrent chemotherapy was unsatisfied. In addition, T4 is the predicting factor of poor prognosis for NPC patients. In this retrospective analysis, the long‐term outcomes IMRT combined by induction chemotherapy deleting concurrent chemotherapy with or without adjuvant chemotherapy for T4 non‐metastatic NPC were analyzed. Materials and Methods From January 2005 to November 2016, a total of 145 biopsy‐proven non‐metastatic T4 NPC was treated with IMRT combined by induction chemotherapy with or without adjuvant chemotherapy. The survival and side effects of the patients were analyzed. Results Median follow‐up time was 74 months (ranges, 8–186 months). 10.0%, 61.3%, 27.3%, and 1.3% developed grade 1, 2, 3, and 4 mucositis during IMRT, respectively. 5.5% and 2.0% patients experienced grade 1 and 2 nausea and vomiting; no patients developed grade 3 or 4 nausea and vomiting. Of 145 patients enrolled, 5‐year and 10‐year overall survival(OS) rates were 73.7% and 53.9%, local progression‐free survival(LPFS) rates were 86.1% and 71.6%, regional progression‐free survival(RPFS) rates were 96.7% and 92.8%, distant metastasis‐free survival (DMFS) rates were 86.7%, 78.2%, respectively. At the last follow‐up, five patients developed cranial nerve injury, one patient developed mandibular bone necrosis, four patients developed temporal lobe injury, four patients developed nasopharyngeal massive hemorrhage (three cases after recurrence and one case without recurrence), and five patients developed second primary tumor. Conclusion The survival outcomes of treating T4 NPC IMRT combined by induction chemotherapy deleting concurrent chemotherapy with or without adjuvant chemotherapy are encouraging. Moreover, mucosal reaction, nausea, and vomiting reaction were reduced during IMRT.


| INTRODUCTION
Nasopharyngeal carcinoma (NPC) is prevalent in South China and Southeast Asia.According to the latest statistics of GLOBAL CANCER OBSERVATORY, 1 there were 62,444 new diagnosed cases of NPC in China, which exceeding the sum of all other Asian countries.3][4][5] Radiotherapy is recognized worldwidely as the primary treatment for non-metastatic NPC and T4 disease is closely associated with poor prognosis.Based on previous literature reports, the 5-year survival rate of T4 NPC was 56.5%-68.2%,][5][6][7] Concurrent chemoradiotherapy was recommended for locally advanced NPC based on the results of twodimensional conventional radiotherapy (2D-CRT) era. 8hile in the era of intensity-modulated radiation therapy (IMRT), improved treatment outcomes and lessened side effects were obtained for NPC patients due to the advantages of distributing highly conformal dose to tumor while sparing the adjacent organs at risk (OARs).3][14][15] When T4 NPC patients suffer from local recurrence after primary treatment, it incurs risks of heavier side effects and graver complications receiving retreatment. 16Therefore, we aimed at investigating the longterm efficacy and toxicities of IC followed by IMRT alone with or without AC in stage T4 NPC.

| Patients
From January 2005 to November 2016, 145 biopsy-proven non-metastatic T4 NPC patients at Fudan University Shanghai Cancer center were retrospectively enrolled.All patients received sequential chemoradiotherapy (IC + IMRT ± AC).Written consents were obtained from all patients, and the study was approved by our institutional Ethics Review Board.Initial workup included complete medical history, physical examination, biochemical and hematological blood tests, nasopharyngeal endoscopy, nasopharyngeal contrast-enhanced magnetic resonance imaging (MRI), neck contrast-enhanced computed tomography (CT)/MRI, and positron emission tomography-CT (PET-CT) or a combination of chest CT, abdominal ultrasound/CT and bone scintigraphy.Additional investigations were only performed for those with suspicious findings.Dental extraction, if deemed necessary, was performed before radiation therapy.All patients enrolled were re-staged according to eighth edition of AJCC staging system.

| Radiotherapy
A thermoplastic mask was used to secure the head, neck, and shoulders of the patients in supine position.Enhanced CT scan was performed to acquire slices from the cranial apex to the 2 cm below lower margin of the clavicle head.The Gross tumor volume (GTV) included nasopharyngeal primary tumor and metastasis lymph nodes.Clinical target volume (CTV) includes GTV and subclinical lesions.All the GTV and CTV must be expanded in all directions by 5 mm as planning target volume (PTV) and then appropriately modified accounting for the patient motion and set-up error.The prescription dose of primary tumor was 66-70.4Gy in 30-32 fractions; the prescribed dose was 66 Gy for positive cervical lymph nodes, 60 Gy for highrisk area, and 54 Gy for low-risk area in the same fraction of the primary tumor.

| Chemotherapy
All patients received IC followed by IMRT alone with or without AC.There are four species of platinum-based chemotherapy regimens, including fluorouracil with cisplatin (PF: DDP 25 mg/m 2 d1-3 + 5-FU 500 mg/m 2 /d d1 adjuvant chemotherapy are encouraging.Moreover, mucosal reaction, nausea, and vomiting reaction were reduced during IMRT.

K E Y W O R D S
deleting of concurrent chemotherapy, intensity-modulated radiotherapy, nasopharyngeal carcinoma, T4 with 120-h infusion), gemcitabine with cisplatin (GP: gemcitabine 1.0 g/m 2 d1, d8 + DDP 25 mg/m 2 d1-3), docetaxel with cisplatin (TP: docetaxel 60 mg/m 2 d1 + DDP 25 mg/m 2 d1-3), and docetaxel with cisplatin plus fluorouracil (TPF: docetaxel 60 mg/m 2 d1 + DDP 25 mg/m 2 d1-3 + 5-FU 500 mg/m 2 /d with 120-h infusion).IMRT was initiated 3 weeks after completion of the IC, as well as AC was administered 4 weeks after radiotherapy.Before each cycle of chemotherapy and during the intermission of chemotherapy, patients performed complete blood count, and blood biochemical parameters.If grade 4 myelosuppression occurs, 20% dose reduction should be administered in the next cycle of chemotherapy.Chemotherapy would be delayed if the hematologic parameters of patients were not reach to standard.Up to a 2-week delay of chemotherapy is allowed, or the chemotherapy will be terminated.

| Evaluation and follow-up
Follow-up intervals: every 3 months within 2 years after completion of treatment, every 6 months from third year through fifth year and annually thereafter.Contents of each follow-up included physical examination, nasopharyngeal MRI, neck CT/MRI, nasopharyngeal endoscopy, and plasma EBV DNA (2018 till now).Chest CT and abdominal ultrasound/CT should be performed at least every 6 months or annually according to patient status.If necessary, increase the inspection frequency and conduct PET-CT inspection.Statistics SPSS 26.0 (SPSS Inc) software was used for data processing.Kaplan-Meier method was used to calculate local progression-free survival (LPFS), regional progressionfree survival (RPFS), distant metastasis-free survival (DMFS) and overall survival (OS).

| Patient characteristics and treatment compliance
There were 145 patients in the whole group, of which 117 were males and 28 were females.The median age was 50 years (range, 21-72 years).The course of disease before treatment in 88 cases was within 6 months, including 53 cases within 3 months.All patients received IC in 2 or 3 cycles with TP, PF, GP, or TPF regimen.As for IMRT course, all completed at the prescribed dose except one did not complete the plan due to non-medical reasons (63.8 Gy/29 F).After IMRT, AC were administrated to 79.3% (115) patients.Details are summarized in Table 1.

| Outcomes
The median follow-up time was 74 months (range, 8-186 months).Among 57 patients of treatment failures, 31 cases were local recurrence, 8 cases were regional recurrence, and 30 cases were distant metastasis (Table 2).Sixty-three patients died at last follow-up, 18 patients died of local recurrence, 18 patients died of distant metastasis, 4 patients died of local and reginal recurrence, 7 patients died of recurrence and distant metastasis, 3 patients died of second primary tumor, 3 patients died of severe nasopharyngeal bleeding, the left patients died of others reasons.5-year and 10-year OS rates were 73.7% and 53.9%, LPFS rates were 86.1% and 71.6%, RPFS rates were 96.7% and 92.8%, DMFS rates were 86.7% and 78.2%, respectively (Figure 1).N stage was significantly correlated with OS and DMFS.The N3 mortality rate (14/19 cases) was high, and the estimated 5-year and 10-year survival rates were 52.6% and 20.8%, respectively.For all enrolled patients, 30 suffered metastasis, and the metastasis rate of N3 was high (11/19).The rates of DMFS at 5 years and 10 years were 61.3% and 37.4%, respectively.The prognosis of T4N3 was significantly worse than T4N0-2 (Table 3).

| Treatment complications
There were no treatment-related deaths during the follow-up.According to RTOG grading criteria, the incidences of grade 1, 2, 3, and 4 acute mucositis were 10.0%, 61.3%, 27.3%, and 1.3%, respectively.52.0% patients received fluid therapy, median fluid therapy time was 6 days (range, 1-18 days), and median weight loss was 8% (range, 0%-30.8%).None of the patients placed a stomach tube.The main late reactions were grade 1-2 xerostomia and hearing impairment; in addition, there are five patients developed cranial nerve injury, one patient developed mandibular bone necrosis, four patients developed temporal lobe injury, four patients developed nasopharyngeal massive hemorrhage (three cases after recurrence and one case without recurrence), and five patients developed second primary tumor (leukemia, liver cancer, lung adenocarcinoma, hypopharyngeal cancer, and esophageal cancer).Radiation experts are in the progress of exploring new treatment scheme for providing equivalent survival benefits with reduced adverse effects and financial burden.
The European Society for Medical Oncology (ESMO) Precision Medicine Working Group proposed several schemes of de-intensifications: ① deletions: forgo one segment of the standard treatment; ② shortened duration of treatment: lessen treatment-related burden and risk of toxicities by reducing treatment duration; ③ combination of the two methods above. 179][20] André et al. conducted a prospective pooled analysis of six randomized phase 3 trials.With a median follow-up of 72.3 months, 3-month of adjuvant chemotherapy was not significantly inferior to 6-month in stage III colon cancer patients in terms of overall survival, and the 5-year overall survival results in favor of 3-month adjuvant chemotherapy should be considered for adoption in clinical context.This conclusion demonstrates that shortened treatment duration is associated with significant reductions in associated toxicity, inconvenience, and cost. 18FAST Forward trial enrolled 4096 breast cancer patients (pT1-3, pN0-1, M0) at 97 hospitals in the United Kingdom.In these patients who were at least 18-year-old and underwent breast conservation surgery or mastectomy, median follow-up was 71.5 months.
6][27][28][29] A noninferiority prospective study based on 332 low-risk III-IVa NPC patients was performed and showed no significant differences on PFS, OS and the cumulative incidences of locoregional relapse or distant metastasis between two cycles and three cycles of DDP-based CCRT groups.Patients in 2 cycles of DDP-based concurrent chemoradiotherapy developed significantly less grade 3-4 mucositis, hyponatremia, hearing impairment and cervical skin fibrosis. 26nother multicenter, randomized, phase 3, non-inferiority clinical trial enrolled 341 low-risk NPC patients (II/T3N0) and divided into IMRT-alone and CCRT group.The 3-year failure-free survival was 90.5% and 91.9% for IMRT-alone and CCRT group, respectively.Similarly, there was no significant difference existed in terms of OS, LPFS, and DMFS.A significantly lower incidence of adverse events especially grade 3 or 4 hematological toxicities (leukopenia, neutropenia) and nonhematological toxicities (nausea, vomiting, anorexia, weight loss, mucositis) were observed in the IMRT-alone group (17% vs. 46%).Simultaneously, the IMRT-alone group had significantly better social function scores during radiotherapy. 27A meta-analysis based on eight articles extracted data from 2605 NPC who received induction chemotherapy plus IMRT (IC + RT) or induction chemotherapy plus concurrent chemoradiotherapy (IC + CCRT), respectively.No statistically significant benefit was observed in terms of overall survival, local recurrence-free survival, and distant metastasis-free survival with IC + CCRT group.The proportion of grade 3-4 hematological toxicity was higher in the IC + CCRT group. 29Therefore, de-intensifying or omitting concurrent chemotherapy in specified NPC patients seemed feasible.In this study, the omission of concurrent chemotherapy achieved satisfactory survival for T4 patients with 5-year OS rates of 73.3%.Dose on target volume was associated with local control significantly.Ng et al. analyzed 193 primary diagnosed non-metastasis NPC patients, of which 93% had Stage III/IV disease.After median follow-up 30 months, they proposed that at least 66.5 Gy to target volumes can lessen locoregional failure significantly. 30The irradiation dose of nasopharyngeal primary tumors is usually limited due to its special anatomical location.T1-3 NPC always have better local tumor control since the target volume can get enough radiation dose without increasing the central nervous system (CNS) exposure.Inversely, advanced T4 is characterized by intracranial extension and/or involvement of CNS.2][33] Forty-one cases of T4 NPC with intracranial invasion were analyzed by Xue.In order to avoid overdose irradiated of CNS, the maximum point dose (D max ) for neurological organs was 55.9 (53.3-58.2) Gy, 43.9 (41.0-45.7)Gy, 56.4 (43.1-59.6)Gy, 54.6 (42.4-60.1)Gy, 54.5 (42.4-58.9)Gy, 65.1 (60.4-68.4),64.7 (58.8-67.6)for brainstem, spinal cord, optic chiasm, affected side of optic nerve, unaffected side of optic nerve, affected side of temporal lobe and unaffected side of temporal lobe, respectively.While the minimum point dose for primary gross target volume was 55.2 (48.3-67.3)Gy, dose to 95% of the target volume was 61.6 (52.6-69.0)Gy. 32 A total of 3328 NPC patients with stage III/IV performed IMRT in Hong Kong public oncology centers, of which 13.2% did not receive chemotherapy, most commonly due to advanced age, poor performance status, and patient's refusal.In phases III and IV, 83.3% and 87.2% received concurrent chemotherapy plus induction/adjuvant chemotherapy, respectively.The 5-year, 8-year LPFS rate and OS for T4 were 76.0%, 71.6% and 63.5%, 51.2% respectively. 3Wu et al. analyzed 614 NPC underwent IMRT and revealed that use of concurrent chemoradiotherapy plus induction/adjuvant chemotherapy was favorable for stage III/IV NPC patients.The 5-year, 10-year LPFS rate and OS for T4 NPC were 83.0%, 79.3%, and 68.1%, 59.2%, respectively. 4In our retrospective investigation, the 5-year and 10-year OS and LPFS rates for T4 NPC who did not receive concurrent chemotherapy were 73.8% and 59.3%, 87.5% and 79.3%, respectively.Similar conclusions have been obtained on other literatures that IMRT without concurrent chemotherapy in local advanced stage.A comparison of 5-year LRFS and OS in T4 NPC among previous studies and our study have been listed in Table 4.
Patients with N3 NPC are at high risk of distant metastasis and poor survival rate.However, few studies dedicated to analyze the effect of N-classification among the T4 subgroup.Lin et al. investigated the survival impacts of various T-classification on N3 stage and revealed that patients with T4 have worse OS (5-year rates, 42.2% vs. 82.8%,p < 0.0001) and DMFS (5-year rates, 57.2% vs. 77.7%,p = 0.0163) while compared with T1-3N3 disease. 36Tsai et al. conducted a study on adjuvant chemotherapy after definitive concurrent chemoradiotherapy for N3 nasopharyngeal cancer.After classified the whole group of patients by T stage, they found that the 5-year OS rate for T4N3 patients was 53.3%. 37Our study reported a 5-year OS rate of 52.6% on the basis of deleting concurrent chemotherapy, which is close to the above two studies.Besides, Lee et al. proposed that the impact of concurrent chemotherapy on improving distant metastasis is insufficient. 38Patients with T4N3 are supposed to incorporate novel agents, such as targeted and immune oncology therapies to improve the treatment outcome.Multiple clinical studies are recruiting, such as Sichuan Cancer Hospital and Institute is performing a prospective, randomized, double-blind, placebo-controlled, multicenter phase II clinical study on the efficacy and safety of combined Nituzumab and IC for locally advanced NPC.Sun Yat-sen University Cancer Center is carrying out a randomized, open-label, phase II study to evaluate the efficacy and safety of Sintilimab plus capecitabine versus capecitabine alone as adjuvant therapy for patients with locoregionally advanced NPC.
Due to the deletion of concurrent chemotherapy during IMRT, decreasing side effects including mucosal reactions, nausea, and vomiting were observed. 28,29,39 locoregional relapse-free survival, and DMFS were 82.5%, 93.4%, and 91.7%, respectively.During IMRT, grades 1, 2, 3, and 4 of mucositis or digestive tract reaction were 53.0%, 31.6%,4.8%, 0% and 7.5%, 3.6%, 2.4%, 0%, respectively. 28ang et al. followed up and analyzed 243 NPC patients who were sequentially treated with IC followed by IMRT and AC, of which 14 cases developed nasopharyngeal recurrence, 2 developed cervical region recurrence, 39 developed distant metastases.The 5-year OS rate of stage III and IVa (AJCC 8th) was 86.5% and 56.5%. 39n summary, retrospective study showed the combination of IMRT with sequential chemotherapy deleting concurrent chemotherapy is an effective method.Prospective studies in low-risk III-IVA and II/T3N0 NPC did not observe significant lower efficacy by deleting concurrent chemotherapy.Our results showed that the combination of IMRT with sequential chemotherapy deleting concurrent chemotherapy in T4 NPC could be regarded as an effective method.Detects in our study were a single center and retrospective study.Future prospective and multicenter studies should be conducted to explore whether deletion of concurrent chemotherapy is possible for nonlow-risk advanced nasopharyngeal carcinoma.

T A B L E 2 8 F
Patterns of treatment failure.I G U R E 1 Kaplan-Meier curves showing overall survival (OS) rates, local progression-free survival (LPFS) rates, regional progression-free survival (RPFS) and distant metastasis-free survival (DMFS) for 145 patients with T4 nasopharyngeal carcinoma.
Patient characteristics of T4 nasopharyngeal carcinoma.
T A B L E 1 Treatment outcomes by N stage.
T A B L E 3 0%) completed one, two, and three/four cycles of induction chemotherapy, respectively.After median follow-up time of 65 months, 5-year estimated rates of OS, The 5-year LRFS and OS in T4 NPC among various studies.